Pyrazoles and pyrazolopyrimidines having CRF antagonistic activity

ABSTRACT

The pyrazoles and pyrazolopyrimidines of the formula                    
     wherein R 1 , R 2 , R 3 , R 4  and A are as defined herein, have corticotropin releasing factor (CRF) antagonist activity. As such, they are effective in the treatment of a wide range of diseases including stress-related illnesses.

This is a divisional of U.S. patent application Ser. No. 08/961,413,Oct. 30, 1997, now U.S. Pat. No. 6,103,900 which is a divisional of U.S.patent application Ser.No. 08/448,529, filed Jun. 14, 1995, now U.S.Pat. No. 5,712,303, issued Jan. 27, 1998, which was a Section 371 filingof PCT/US93/10359, filed Nov. 3, 1993 which was a continuation in partof U.S. patent application Ser. No. 07/992,225, filed Dec. 17, 1992, nowabandoned.

This invention relates to pyrazoles and pyrazolopyrimidines,pharmaceutical compositions containing them, and methods ofadministering them to subjects in need of their corticotropin-releasingfactor (CRF) antagonist activity.

CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245referring to peptides and pyrazolinones, respectively. The importance ofCRF antagonists is set out in the literature, e.g. as discussed in U.S.Pat. No. 5,063,245, which is incorporated herein by reference. A recentoutline of the different activities possessed by CRF antagonists isfound in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473(1991), also incorporated herein by reference. Based on the researchdescribed in these two and other references, CRF antagonists areeffective in the treatment of a wide range of diseases includingstress-related illnesses, such as stress-induced depression, anxiety,and headache; abdominal bowel syndrome; inflammatory diseases; immunesuppression; human immunodeficiency virus (HIV) infections; Alzheimer'sdisease; gastrointestinal diseases; anorexia nervosa; hemorrhagicstress; drug and alcohol withdrawal symptoms; drug addiction, andfertility problems.

The compound of formula I below wherein A is C═O, R₁ is amino, R₂ ismethylthio, R₃ is 2-chlorophenyl, and R₄ is 2,4,6-trichlorophenyl is acommercial compound of no known utility.

The present invention relates to a compound of the formula

and the acid addition salts thereof, wherein

A is C═O or SO₂, or A and R₁ together with the carbons to which they areattached form pyrimidinyl or 5-pyridyl which may be substituted by R₅which is hydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, hydroxy, amino,O(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), SH,S(O)_(n)(C₁-C₆ alkyl) wherein n=0, 1 or 2, wherein said C₁-C₆ alkyl maybe substituted by from 1 to 3 substituents R₆ which is hydroxy, amino,C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,NH(C═O)CH₃, fluoro, chloro, bromo or C₁-C₃ thioalkyl;

R₁ is hydrogen, C₁-C₆ alkyl, amino, O(C₁-C₆ alkyl), NH(C₁-C₆ alkyl),N(C₁-C₆ alkyl)(C₁-C₆ alkyl), wherein said C₁-C₆ alkyl may be substitutedby from 1 to 3 substituents R₆ as defined above;

R₂ is hydrogen, C₁-C₆ alkyl, hydroxy, amino, O(C₁-C₆ alkyl), NH(C₁-C₆alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), SH, S(O)_(n)(C₁-C₆ alkyl) whereinn=0, 1, or 2, cyano, hydroxy, carboxy, or amido, wherein said alkyls maybe substituted by one to three of hydroxy, amino, carboxy, amido,NH(C═O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), (C═O)O(C₁-C₆alkyl),C₁-C₃alkoxy, C₁-C₃thioalkyl, fluoro, bromo, chloro, iodo, cyano ornitro;

R₃ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 9 to 12 membered bicycloalkyl,optionally containing one to three of O, S or N—Z wherein Z is hydrogen,C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl or phenylmethyl, wherein each one ofthe above groups may be substituted independently by from one to threeof fluoro, chloro, bromo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or trifluoromethyl,or one of cyano, nitro, amino, NH(C₁-C₆ alkyl), N(C₁-C₄ alkyl)(C₁-C₂alkyl), COO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), SO₂NH(C₁-C₄ alkyl),SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), SO₂NH₂, NHSO₂(C₁-C₄ alkyl), S(C₁-C₆alkyl), SO₂(C₁-C₆ alkyl), wherein said C₁-C₄ alkyl and C₁-C₆ alkyl maybe substituted by one or two of fluoro, chloro, hydroxy, amino,methylamino, dimethylamino or acetyl; and

R₄ is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl,benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl,azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl,morpholinyl, pyridinyl, tetrazolyl, or 3 to 8-membered cycloalkyl or 9to 12-membered bicycloalkyl, optionally containing one to three of O, Sor N—Z wherein Z is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkanoyl, phenyl orphenylmethyl, wherein each of the above groups may be substitutedindependently by from one to three of fluoro, chloro, bromo,trifluoromethyl, C₁-C₆ alkyl or C₁-C₆ alkoxy, or one of cyano, nitro,amino, NH(C₁-C₆ alkyl), N(C₁-C₄ alkyl)(C₁-C₂ alkyl), COO(C₁-C₄ alkyl),CO(C₁-C₄ alkyl), SO₂NH(C₁-C₄ alkyl), SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl),SO₂NH₂, NH₂SO₂(C₁-C₄ alkyl), S(C₁-C₆ alkyl), SO₂(C₁-C₆ alkyl), whereinsaid C₁-C₄ alkyl and C₁-C₆ alkyl may be substituted by one or two offluoro, chloro, hydroxy, amino, methylamino, dimethylamino or acetyl;provided that (1) R₄ is not unsubstituted phenyl; (2) when R₁ is amino,R₂ is methylthio, R₄ is 2,4,6-trichlorophenyl, and A is C═O, then R₃ isnot 2-chlorophenyl; and (3) R₁ and R₂ are not both hydrogen.

More specific compounds of the formula I include those wherein R₃ isphenyl substituted independently with one or two of fluoro, chloro,bromo, methyl, trifluoromethyl, nitro, C₁-C₆ alkyl, C₁-C₆ alkyloxy,SO₂NH₂, SO₂NH(C₁-C₆ alkyl), SO₂N(C₁-C₆ alkyl)₂, or R₃ is primary,secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C₄-C₉alkyl may contain from one to two double or triple bonds and may besubstituted by from 1 to 3 substituents R₆ which is hydroxy, amino,C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,NH(C═O)CH₃, fluoro, chloro, bromo, or C₁-C₃ thioalkyl.

More specific compounds of the formula I are those wherein A is C═O,those wherein R₁ is amino, methylamino or dimethylamino; those whereinR₂ is ethyl or methylthio and those wherein R₄ is 2,4,6-trichlorophenyl,2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or4-bromo-2,6-dimethylphenyl.

More specific compounds of formula I further include those wherein R₃ isphenyl which may be substituted at positions 2 or 5 with one or two ofmethyl, C₂-C₆ straight-chain or branched alkyl, trifluoromethyl, fluoro,chloro, bromo or nitro, those wherein A and R₁ together form apyrimidine ring, such that the bicyclic structure formed ispyrazolo[3,4-d]pyrimidine, and R₅ is substituted at the 6 position; andthose wherein R₃ is phenyl substituted independently with one or two offluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C₁-C₆ alkyl,C₁-C₆ alkyloxy, SO₂NH₂, SO₂NH(C₁-C₆ alkyl), or SO₂N(C₁-C₆alkyl)₂, R₄ is2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl,2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl, andR₂ is methylthio, methyl or ethyl.

More specific compounds of formula I also include those wherein R₃ isphenyl substituted independently with one or two of fluoro, chloro,bromo, methyl, trifluoromethyl, nitro, C₁-C₆ alkyl, C₁-C₆ alkyloxy,SO₂NH₂, SO₂NH(C₁-C₆ alkyl), SO₂N(C₁-C₆ alkyl)₂, or R₃ is primary,secondary or tertiary alkyl of from 4-9 carbon atoms wherein said C₄-C₉alkyl may contain from one to two double or triple bonds and may besubstituted by from 1 to 3 substituents R₆ which is hydroxy, amino,C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino, ethylamino,NH(C═O)CH₃, fluoro, chloro, bromo or C₁-C₃ thioalkyl; R₄ is2,4,6-trichlorophenyl, 2,4,6-trimethylphenyl,2,6-dichloro-4-trifluoromethylphenyl or 4-bromo-2,6-dimethylphenyl; R₁is amino, methylamino or dimethylamino; and R₂ is methylthio or ethyl.

The most preferred compounds of the invention are

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-bis-trifluoromethylphenyl)methanone,

[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,

[5-amino-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-4-yl]-(5-isopropyl-2-methylphenyl)methanone,and

[5-amino-1-(4-bromo-2,6-dimethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dibromophenyl)methanone.

The invention also relates to a composition for the treatment ofillnesses induced or facilitated by corticotropin releasing factor whichcomprises a compound of the formula I as defined above or the knowncompound of formula I wherein A is C═O, R₁ is amino, R₂ is methylthio,R₃ is 2-chlorophenyl, and R₄ is 2,4,6-trichlorophenyl, in an amounteffective in the treatment of said illnesses, and a pharmaceuticallyacceptable carrier, and to a composition for the treatment ofinflammatory disorders, stress and anxiety related disorders includingstress-induced depression and headache, abdominal bowel syndrome, immunesupression, HIV infections, Alzheimer's disease, gastrointestinaldiseases, anorexia nervosa, hemorrhagic stress, drug and alcoholwithdrawal symptoms, drug addiction, and fertility problems, whichcomprises a compound of the formula I as well as the known compound,both as defined above in an amount effective in the treatment of saiddisorders, and a pharmaceutically acceptable carrier. More specific andmost preferred compositions for the treatment of such illnesses anddisorders comprise a more specific and most preferred compound offormula I as defined above.

The invention further includes a method for the treatment of illnessesinduced or facilitated by corticotropin releasing factor byadministering to a subject in need of such treatment a compound offormula I or the known compound, both as defined above, and a method forthe treatment of stress and anxiety related disorders, includingstress-induced depression and headache, abdominal bowel syndrome,inflammatory disorders, immune suppression, HIV infections, Alzheimer'sdisease, gastrointestinal diseases, anorexia nervosa, hemorrhagicstress, drug and alcohol withdrawal symptoms, drug addiction, andfertility problems, particularly depression, by administering to asubject in need of such treatment a compound of formula I as well as theknown compound, both as defined above. More specific and most preferredmethods for the treatment of such illnesses and disorders comprise amore specific and most preferred compound of formula I as describedabove.

Whenever reference is made herein to C₁-C₆ alkyl, a straight or branchedchain alkyl of one to six carbon atoms is meant, such as methyl, ethyl,isopropyl or hexyl.

Whenever reference is made herein to C₁-C₆ alkyl, in the definition ofR₅ and R₁, this includes unsaturated C₂-C₆ alkyl, such as C₂-C₆ alkylhaving one double or triple bond, C₃-C₆ alkyl having two double bonds,and C₄-C₆ alkyl having two triple bonds.

Whenever reference is made hereafter to a compound of formula I, thisincludes the known compound of formula I as described above.

Whenever R₃ is a heterocyclic group, the attachment to A, defined above,is through one of the carbons in the heterocyclic group. Similarly, whenR₄ is a heterocyclic group, the attachment to the nitrogen in thepyrazole ring is through one of the carbons in the heterocyclic group.

Whenever reference is made herein to 3- to 8-membered cycloalkyl or 9-to 12-membered bicycloalkyl containing one to three of O, S or N—Z, itis understood that the oxygen and sulfur ring atoms are not adjacent toeach other.

The compounds of the formula I wherein R₁ is amino or C₁-C₆ alkyl, andR₂ is methylthio, having the formula II (not shown), may be preparedfrom a compound of the formula

wherein R₁₀ is cyano or C(O)(C₁-C₆ alkyl) and A and R₃ are as definedabove with reference to formula I, by reaction with a compound of theformula

R₄—NHNH₂  IV

wherein R₄ is as defined with reference to formula I. This reaction isgenerally carried out in a polar solvent, such as a C₁-C₆ alcohol. Thereaction temperature generally ranges from about 20° C. to about 160°C., and is conveniently the reflux temperature of the reaction mixture.

The compounds of formula III may be prepared by treating a compound ofthe formula

R₃—A—CH₂R₁₀  V

with a base such as sodium hydride, in the presence of carbon disulfidefollowed by reaction of the formed intermediate with methyl iodide in areaction solvent such as dimethylsulfoxide.

The compounds of formula IV are readily available or may be obtained bymethods known in the art.

The compounds of formula V may be prepared by known methods.

The compounds of the formula I wherein R₂ is alkoxy, amino, or mono- ordisubstituted amino may be prepared by using the above procedure withR₄NHNH₂ from the corresponding compounds of the formula

wherein A and R₃ are as defined with reference to formula I, R₁₀ is asdefined with reference to formula III, and R, R′ and R″ are eachhydrogen or C₁-C₆ alkyl in accordance with the definition of R₂ above.

The compounds of the formula I wherein R₁ is C₁-C₆ alkoxy or C₁-C₆alkylthio and R₂ is C₁-C₆ alkyl may be prepared from a compound of theformula

wherein R_(x) is chloro or bromo, R₂ is C₁-C₆ alkyl, and R₃, R₄ and Aare as defined above with reference to formula I, with a C₁-C₆ alcoholor C₁-C₆ mercaptan in the presence of a base. The reaction is generallycarried out in a polar solvent such as ethanol or t-butanol attemperatures from about 20° C. to about 160° C. and conveniently roomtemperature.

The compounds of the formula IX may be prepared by treating a compoundof the formula

with a halogenating agent such as thionlyl chloride or bromide, orphosphorous oxychloride or pentachloride, or phosphorous oxybromide orpentabromide. The reaction may be carried out without a solvent or in anaprotic solvent such as methylene chloride, or dichloroethane attemperatures of about 0° C. to about 100° C.

Compounds of formula X may be prepared by treating compounds of theformula

with an activated derivative of a carboxylic or sulfonic acid of theformula R₃AOH, such as an acid chloride of the formula R₃ACl wherein R₃and A are as defined with reference to formula I, in the presence ofcalcium hydroxide in an aprotic solvent such as dioxane as described inJensen, Acta Chem. Scand., 13, 1668-1670 (1959) at temperatures of fromabout 20° C. to about 100° C. Compounds of the formula XI are known inthe art.

The compounds of the formula I wherein R₁ is C₁-C₆ alkoxy or C₁-C₆alkylthio and R₂ is C₁-C₆ alkylthio may be prepared from a compound ofthe formula

wherein R_(Y) is chloro or bromo and R₃, R₄ and A are as defined abovewith reference to formula I, with a C₁-C₆ alcohol or C₁-C₆ mercaptan inthe presence of a base. The reaction is generally carried out in a polarorganic solvent such as ethanol or t-butanol at temperatures from about20° C. to about 160° C., conveniently room temperature.

The compounds of the formula XII may be prepared from a compound of theformula

by reaction with a halogenating agent such as thionyl chloride orbromide, or phosphorous oxychloride or pentachloride, or phosphorousoxybromide or pentabromide. The reaction may be carried out with asolvent or in an aprotic solvent such as methylene chloride ordichloroethane at temperatures of about 0° C. to about 100° C.

The compounds of the formula XIII may be prepared by treating a compoundof the formula

with activated benzoic or sulfonic acid derivatives, conveniently anacid chloride, in the presence of calcium hydroxide in an aproticsolvent such as dioxane as described in the above reference by Jensen.

The compounds of the formula XIV may be prepared by treating a compoundof the formula

wherein R_(z) is chloro, bromo with a C₁-C₆ mercaptan in the presence ofa base. The reaction is generally carried out in a polar organic solventsuch as t-butanol at temperatures from about 20° C. to about 160° C.,conveniently the reflux temperatures of the reaction mixture.

The compounds of the formula XV may be prepared from compounds of theformula

with a halogenating agent such a thionyl chloride or bromide, orphosphorous oxychloride or pentachloride, or phosphorous oxybromide orpentabromide. The reaction may be carried out without a solvent or in anaprotic solvent such as methylene chloride or dichloroethane attemperatures of about 0° C. to about 100° C.

The compounds of the formula I wherein R₁ is C₁-C₆ alkoxy or C₁-C₆alkylthio and R₂ is C₁-C₆ alkoxy may be prepared from a compound of theformula

wherein R_(XX) is chloro or bromo, R₂ is C₁-C₆ alkoxy and R₃, R₄ and Aare as defined above with reference to formula I, with a C₁-C₆ alcoholor C₁-C₆ mercaptan in the presence of a base. The reaction is generallycarried out in a polar organic solvent such as ethanol or t-butanol attemperatures from about 20° C. to about 160° C., conveniently the refluxtemperature of the reaction mixture.

The compounds of the formula XVII may be prepared from a compound of theformula

by reaction with a halogenating agent such as thionyl chloride orbromide, or phosphorous oxychloride or pentachloride, or phosphorousoxybromide or pentabromide. The reaction may be carried out without asolvent or in an aprotic solvent such as methylene chloride, ordichloroethane at temperatures of about 0° C. to about 100° C.

The compounds of the formula XVIII may be prepared by treating acompound of the formula

with an activated derivative of a carboxylic or sulfonic acid of theformula R₃AOH, conveniently an acid chloride of the formula R₃AClwherein R₃ and A are as defined above with reference to formula I, inthe presence of calcium hydroxide in an aprotic solvent such a dioxaneas described by Jensen in the reference cited above.

The compounds of the formula XIX may be prepared by treating a compoundof the above formula XV with an alcohol in the presence of a base. Thereaction is generally carried out in a polar organic solvent such asethanol at temperatures from about 20° C. to about 160° C., convenientlythe reflux temperatures of the reaction mixture.

The compounds of the formula I wherein R₁ is amino and R₂ isO(C₁-C₆alkyl) may be prepared by reacting a compound of the formula

wherein R₃, R₄ and A are as defined above with reference to formula I,with hydrazine in a solvent such as a C₁-C₆ alcohol, conveniently at theboiling point of the solvent.

The compounds of the formula XX may be prepared by treating a compoundof the formula

wherein R₃, R₄ and A are as defined above with reference to formula I,with an alkylating agent such as di(C₁-C₆ alkyl) sulfate, and a basesuch as sodium hydride, in a solvent such as dimethylsulfoxide.

The compounds of the formula XXI may be prepared by treating a compoundof the formula

with an activated derivative of a carboxylic or sulfonic acid of theformula R₃AOH such as an acid chloride of the formula R₃ACl, wherein R₃and A are as defined with reference to formula I, in the presence of aLewis acid such as aluminum chloride in an aprotic solvent such asmethylene chloride, dichloroethane, or tetrachloroethane, attemperatures of about 0° C. to about 150° C.

The compounds of the formula XXII may be prepared by treatment of acompound of the formula

with phthalic anhydride in acetic acid at the boiling point of thesolvent.

The compounds of the formula XXIII may be prepared by contactingcyanoacetyl chloride with R₄NHNH₂ in the presence of a base followed byheating the resulting hydrazide at reflux in alcoholic solution in thepresence of a base.

The compounds of formula I wherein A and R₁ are taken together to formpyrimidinyl have the formula

wherein R₂, R₃, R₄, and R₅ are as defined above with reference toformula I. These compounds may be prepared by cyclization of a compoundof the above formula I wherein A is C═O and R₁ is amino with a compoundof the formula

wherein R₅ is as defined with reference to formula I. This reaction isgenerally carried out at 100 to 250° C., and conveniently at the refluxtemperature of the compound XXV.

The compounds of formula I wherein A and R₁ are taken together to form5-pyridyl have the formula

wherein R₂, R₃, R₄ and R₅ are as defined with reference to formula I.These compounds may be prepared as shown in Reaction Scheme 1.

The compounds of formula XXIX are prepared by reacting a ketone of theformula XXVII with a compound of the formula XXVIII in a suitablesolvent such as tetrahydrofurane in the presence of a base such assodium hydride. The reaction is conveniently carried out at the refluxtemperature of the reaction mixture.

The compound XXIX is reacted with a compound of the formula R₂C(OCH₃)₃to form the compound XXX. The reaction is carried out in a suitablesolvent such as ethyl acetate, conveniently at the reflux temperature ofthe reaction mixture. The wavy line in formula XXX indicates that eitherisomer of this compound is included, in accordance with acceptedconvention for indicating stereoisomers.

The compound XXXI is prepared by reacting compound XXX with a hydrazineof the formula H₂NNHR₄ wherein R₄ is as defined with reference toformula I. The reaction is carried out in a suitable solvent such asethanol, conveniently at the reflux temperature of the reaction mixture.

The compounds of formula XXVI wherein R₅ is linked to position 6 isformed by first reacting compound XXXI with hydrazine hydrate in asuitable solvent such as ethanol, conveniently at the reflux temperatureof the reaction mixture. The compound XXXII is separated fromprecipitated phthalhydrazide and taken up in an organic solvent such astoluene. The compound XXVI is formed by dehydrogenation of compoundXXXII with palladium over carbon.

Reaction Scheme 1 shows the preparation of compounds XXVI wherein R₅ isin the 6-position. A similar reaction sequence may be followed toprepare compounds XXVI wherein R₅ is in the 7-position by replacingcompound XXVIII by a compound of the formula

The compounds of formula I wherein A is C═O and R₁ and R₂ are the samegroup R₇ may be prepared by reacting a β-ketone of the formula

with the hydrazine of the formula IV as defined above to form a pyrazolecompound of the formula

The reaction proceeds at reflux in an appropriate solvent such asethanol. After bromination of the pyrazole compound, e.g. with brominein acetic acid, to form the corresponding 4-bromo derivative andconventional metallation, e.g. with t-butyl lithium, at −78° C. intetrahydrofuran, a suitably activated R₃ carboxylic acid such as theacid chloride R₃C(O)Cl is added to give the desired compound I.

The compounds of formula I wherein A is C═O and R₁ and R₂ are not thesame, and wherein R₁ or R₂ is attached through a C₂H₄ fragment, may beprepared from a pyranone of the formula

wherein R₃ is as defined above, and R₂ is as defined above when R₁₁ isC₃-C₆ alkyl which may be substituted by 1 to 3 of R₆, or R₂ is R₁ whenR₁₁ is C₃-C₆ alkyl which may be substituted by one to three of hydroxy,amino, carboxy, amido, NH(C═O)(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆alkyl), (C═O)O(C₁-C₆), C₁-C₃ alkoxy, C₁-C₃ thioalkyl, fluoro, bromo,chloro, iodo, cyano or nitro. The compound XXXIV is reacted with ahydrazine of the formula H₂NNHR₄ wherein R₄ is as defined above to formcompounds of the formulae

which on dehydration and hydrogenation result in compounds of theformulae

The compounds of the formula I wherein A is C═O and R₂ is O(C₁-C₆ alkyl)may be prepared by reacting a hydrazine of the formula R₄NHNH₂ with acompound of the formula (A) in a suitable solvent

such as THF or methylene chloride and cyclization of the resultinghydrazide with heat to give the intermediate (B). This compound may bereacted with an activated carboxyclic acid derivative such as the acidchloride R₃(C═O)Cl in the presence of a Lewis acid such as aluminumtrichloride in a solvent such as ethylene dichloride at temperatures offrom about −10° C. to about 80° C. The formed compound of formula Iwherein R₂ is hydroxy may be reacted with (C₁-C₆ alkyl)L wherein L is aleaving group such as chloro, bromo, or tosylate and C₁-C₆ alkyl may besubstituted in accordance with the substituents in the definition of R₂.

Those compounds of formula I wherein R₁ is C₁-C₆ alkylamino or di(C₁-C₆alkyl)amino may be prepared from corresponding compounds of formula Iwherein R₁ is amino. When R₁ is methylamino or dimethylamino, reactionis with a methylating agent such as methyl iodide. When R₁ is C₂-C₆alkylamino or di(C₂-C₆ alkyl)amino, reaction is with an alkylating agentsuch as C₂-C₆ alkyl-L wherein L is a leaving group such as chloro,bromo, tosylate, or mesylate. Both the methylation and the C₂-C₆alkylation is in the presence of a base such as sodium hydride and asolvent such as tetrahydrofuran, dimethyl formamide or dimethylsulfoxide.

The acid addition salts are prepared in a conventional manner bytreating a solution or suspension of the free base of formula I with onechemical equivalent of a pharmaceutically acceptable acid. Conventionalconcentration or crystallization techniques are employed in isolatingthe salts. Illustrative of suitable acids are acetic, lactic, succinic,maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic,fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic,sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic,p-toluenesulfonic, and related acids.

The compound of the invention may be administered alone or incombination with pharmaceutically acceptable carriers, in either singleor multiple doses. Suitable pharmaceutical carriers include inert soliddiluents or fillers, sterile aqueous solution and various organicsolvents. The pharmaceutical compositions formed by combining the novelcompounds of formula I and the pharmaceutically acceptable carriers arethen readily administered in a variety of dosage forms such as tablets,powders, lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if desired, contain additionalingredients such as flavorings, binders, excipients and the like. Thus,for purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch, alginic acid and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules. Preferred materials for thisinclude lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin andcombinations thereof.

For parenteral administration, solutions of the novel compound offormula I in sesame or peanut oil, aqueous propylene glycol, or insterile aqueous solution may be employed. Such aqueous solutions shouldbe suitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. These particular aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal administration. The sterile aqueousmedia employed are all readily available by standard techniques known tothose skilled in the art.

Additionally, it is possible to administer the compounds of the presentinvention topically when treating inflammatory conditions of the skinand this may be done by way of creams, jellies, gels, pastes andointments, in accordance with standard pharmaceutical practice.

The effective dosage for the compound of formula I depends on theintended route of administration and other factors such as age andweight of the patient, as generally known to a physician. The dosagealso depends on the illness to be treated, although in general the dailydosage will range from about 0.1 to 50 mg/kg of the body weight of thepatient. More specifically, the daily dosage for stress-inducedillnesses will generally range from about 0.1 to 50 mg/kg of the bodyweight of the patient to be treated, for treatment of inflammatorydiseases about 0.1 to about 100 mg/kg will be needed, for Alzheimer'sdisease, about 0.1 to about 50 mg/kg, as well as for gastrointestinaldiseases, anorexia nervosa, hemorrhagic stress, and drug and alcoholwithdrawal symptoms.

The methods for testing the compounds for formula I for their CRFantagonist activity are according to the procedures of Endocrinology,116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985) which determinethe binding activity of a test compound to a CRF receptor. The bindingactivity for the compounds of formula I generally ranges from about 0.2nanomolar to about 10 micromolar.

The following abbreviations are used in the Examples: Ph=phenyl;iPr=isopropyl; HRMS=high resolution mass spectrum.

EXAMPLE 1 A. 2-Bromo-2′,5′-dimethylacetophenone

A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g (0.105 mol)of α-bromoacetyl chloride in 300 mL of 1,2-dichloroethane was cooled inan ice bath under an atmosphere of dry N₂ and treated portionwise with14.15 g (0.106 mol) of aluminum chloride. The reaction mixture wasstirred for 30 minutes at 0-5° C. and then for 2.5 hours at roomtemperature. The mixture was then poured onto ice and the aqueous layerwas acidified with concentrated HCl. The organic layer was separated andthe aqueous layer was extracted twice with methylene dichloride. Thecombined organic extracts were dried with brine solution and withmagnesium sulfate. The solvent was evaporated to give 23.87 g of anamber oil which was for use in the next reaction without furtherpurification.

B. 2-Cyano-2′,5′-dimethylacetophenone

The product of the above reaction (approximately 0.10 mol) was dissolvedin 300 mL of ethanol and was treated with a solution of 16.25 g (0.25mol) of potassium cyanide in 30 mL of water and the resulting mixturewas refluxed for 90 minutes. After cooling, the ethanol was strippedfrom the mixture on the rotary evaporator and the residues were madeslightly acidic with concentrated hydrogen chloride. The product wasextracted into ethyl acetate using precautions to avoid escape ofhydrogen cyanide. The organic extracts were dried with brine and withmagnesium sulfate and evaporated to a gummy semi-solid. This wastriturated repeatedly with hot hexane which, on cooling, depositedneedles to give the desired product, 8.50 g (49% for the two reactions),m.p. 75-76° C.

C. 3,3-Bis-methylthio-2-(2,5-dimethylbenzoyl)-acrylonitrile

A solution of 4.96 g (28.6 mmol) of 2-cyano-2′,5′-dimethylacetophenonein 120 mL of dry dimethyl sulfoxide and 3.43 mL (57.3 mmol) of carbondisulfide in a flame-dried 3-neck round bottom flask under dry nitrogenwas stirred at 15-18° C. while 1.41 g (58.7 mmol) of oil free sodiumhydride was added in 5 portions. The resulting deep red solution wasstirred for 1 hour at 18° C. and then cooled to 15° C. whereupon 3.92 mL(8.95 g, 63.0 mmol) of methyl iodide was added dropwise. The temperaturerose to about 22° C. during the addition. After stirring for 2 hours atroom temperature, the reaction mixture was poured into cold water andthe aqueous layer was extracted three times with ethyl acetate. Thecombined extracts were washed three times with water and then dried withbrine and magnesium sulfate. Evaporation gave 8.96 g of the titlecompound as a heavy orange oil which crystallized in the refrigerator.The analytical sample crystallized from ethanol, m.p. 74.5-75.5° C.

D.5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,5-dimethylbenzoyl)-3-methylthiopyrazole

A suspension of 7.94 g (28.6 mmol) of the product of step C and 7.01 g(28.6 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 100 mLof ethanol was heated at reflux for 2 hours, solution occurring as thereaction mixture was warmed. Then the ethanol was mostly removed on therotary evaporator and the residues were partitioned between diluteaqueous hydrogen chloride solution and ethyl acetate. The organic phasewas washed once with water and with brine, then dried with magnesiumsulfate and treated with decolorizing carbon. The filtered solution wasevaporated and the residues crystallized from 10:1 hexane/ethyl acetateto give 12.00 g (88%) of the title product in two crops, m.p. 130-132°C.

EXAMPLE 25-Methylamino-4-(2-chlorobenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazoleand5-dimethylamino-4-(2-chlorobenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)-pyrazole

A mixture of 0.50 g (1.16 mmol) of5-amino-4-(2-chlorobenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazolein 5 mL of tetrahydrofuran was treated with 50 mg (1.16 mmol) of sodiumhydride and stirred at room temperature for 30 minutes. Then 0.75 ml(1.71 g, 12.0 mmol) of methyl iodide was added dropwise and the reactionmixture was stirred for 60 minutes at room temperature. The reactionmixture was then quenched with water and the products were extractedinto ethyl acetate. Concentration of the dried solution andchromatography on silica gel with mixture of hexane and ethyl acetategave the less polar dimethylamino title compound (300 mg, 54%) as awhite foam.

Anal. Calcd. for C₁₉H₁₅ON₃SCl₄: C, 48.02; H, 3.18; N, 8.88. Found: C,47.84; H, 3.09; N, 9.01.

The more polar monomethyl title compound was isolated from the column inlike manner as a white foam (34 mg, 6%).

Anal. Calcd. for C₁₈H₁₃ON₃SCl₄: C, 46.88; H, 2.84; N, 9.11. Found: C,46.54; H, 2.89; N, 9.07.

EXAMPLE 35-Amino-4-(2-methoxybenzoyl)-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole

To a solution of 2-methoxyphenylmagnesium bromide prepared from 18.7 g(0.10 mol) of 2-bromoanisole and 2.43 g (0.10 mol) of magnesium turningsin ether under dry nitrogen was added 1.6 g (5.0 mmol) of5-amino-4-cyano-3-methylthio-1-(2,4,6-trichlorophenyl)pyrazole and theresulting mixture was stirred and refluxed for 16 hours. Upon cooling,the reaction was decomposed with 50 mL of saturated ammonium chloridesolution. The organic phase was extracted with aqueous hydrogen chlorideand the acidic extract was treated with 10 mL of concentrated hydrogenchloride and heated at 80-90° C. for 10 minutes after which the mixturewas cooled and made alkaline. Extraction with methylene dichloride andchromatography of the extracts with mixtures of hexane and ethyl acetategave 313 mg (14%) of the title compound, m.p. 200-202° C.

Anal. Calcd. for C₁₈H₁₄O₂N₃SCl₃: C, 48.82; H, 3.18; N, 9.49. Found: C,48.54; H, 3.32; N, 9.09.

EXAMPLE 4 A. 5-Amino-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole

To a solution of 0.51 g (22.0 mmol) of sodium in methanol was added 1.66g (20.0 mmol) of 5-methylisoxazole. The reaction mixture as refluxed for8 hours and then stirred overnight at room temperature. Then 4.23 g(20.0 mmol) of 2,4,6-trichlorophenylhydrazine was added and the reactionmixture was again refluxed for 4 hours. A second portion of sodium inmethanol was added and reflux was continued for 24 hours. The reactionmixture was taken up with ether and dilute hydrogen chloride. Theorganic extracts were washed with dilute hydrogen chloride and brine,and then dried with magnesium sulfate and evaporated to give crystals,m.p. 132-134° C. Analysis of this material, particularly two CN bands inthe IR spectrum at 2190 cm⁻¹ and 2250 cm⁻¹, revealed it to be a mixtureof the cis- and trans-isomers of1-cyanoacetone-2,4,6-trichlorophenylhydrazone. This material wassuspended in methanol and treated with 10.0 mmol of sodium methoxide in5 mL of methanol. After 5 minutes at room temperature, water was addedto crystallize the product which was filtered off and washed well withwater. After air drying, the product weighed 2.21 g (40%) and melted at134.0-135.5° C. Despite the similarity in melting points, the lattermaterial was distinctly different from the former, having an R_(f) of0.67 vs. 0.78 for the intermediate on silica gel TLC plates developedwith 1:1 hexane ethyl acetate and a distinctly different 300 MHz protonNMR spectrum.

B.5-(2-Chlorobenzamido)-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole

A suspension of 2.34 g (17.50 mmol) of aluminum trichloride in 20 mL of1,1,2,2-tetrachloroethane was treated with 2.02 mL (2.78 g, 15.9 mmol)of 2-chlorobenzoyl chloride and the resulting solution was stirred for20 minutes at room temperature. Then 2.00 g (7.23 mmol) of the productof Step A was added and the reaction mixture was refluxed for 16 hours.The cooled reaction mixture was poured over ice and the insolubles werefiltered off and washed with ethyl acetate. The organic layer wasseparated and the aqueous was washed twice with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate andevaporated. The residues were chromatographed on silica gel, elutingwith 4:1 hexane ethyl acetate to give 2.05 g (51%) of the title product,an amorphous foam.

Anal. Calcd. for C₂₄H₁₄O₂N₃Cl₅: C, 52.06; H, 2.55; N, 7.593. Found: C,52.11; H, 2.57; N, 7.27.

C. 5-Amino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole

A solution of 1.94 g (3.50 mmol of the product of Step B in 20 mL ofglacial acetic acid was treated with 20 mL of 48% hydrogen bromide andstirred at reflux for 8 hours. The cooled reaction mixture was treatedwith water to crystallize the product which was separated by filtration,washed with water and air dried to give the title product, 1.45 g(100%), m.p. softens about 210° C. and melts at 222° C.

Anal. Calcd. for C₁₇H₁₁ON₃Cl₄: 412.9656. Found: 412.9722.

EXAMPLE 55-Methylamino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)pyrazoleand5-dimethylamino-4-(2-chlorobenzoyl)-3-methyl-1-(2,4,6-trichlorophenyl)pyrazole

A solution of 0.208 g (0.5 mmol) of the compound of Example 4C in 20 mLof tetrahydrofuran (THF) was stirred in an ice/water bath while 5.0 mLof 1.0 M sodium hexamethyldisilazide in THF was added followed by 0.5 mL(1.14 g, 8 mmol) of methyl iodide. The reaction mixture was then stirredovernight at room temperature. The reaction mixture was poured intowater and the products were extracted into ethyl acetate, dried andconcentrated. The residues were chromatographed on silica gel using 5:1hexane/ethyl acetate as eluent to give the less polar dimethylaminotitle compound, 52 mg (23%), m.p. 108-109° C. (ether/pentane).

The more polar product likewise crystallized from ether/pentane to give39 mg (18%) of the monomethylamino title compound, m.p. 174-175° C.

EXAMPLE 65-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,5-dimethylbenzoyl)-3-(n-propyl)pyrazole

A solution of 0.52 g (3.0 mmol) of 2,5-dimethylbenzoylacetonitrile, 0.45g (3.0 mmol) of trimethylorthobutyrate and 0.632 g (0.58 mL, 6.2 mmol)of acetic anhydride in 5.0 mL of ethyl acetate was refluxed overnightand then cooled. The solvents were removed in vacuo and the residueswere dissolved in 10 mL of ethanol. One-half of this solution,containing 1.5 mmol of1-cyano-1-(2,5-dimethylbenzoyl)-3-methoxy-1-pentene was mixed with 0.7mL (0.51 g, 5.0 mmol) of triethylamine and 0.37 g (1.50 mmol) of2,6-dichloro-4-trifluoromethylphenylhydrazine and refluxed for 2.5hours. The reaction mixture was cooled and partitioned between dilutehydrogen chloride and ethyl acetate. The organic phase was washed withwater and then dried with brine and with magnesium sulfate. The solventwas evaporated to give an oil which was chromatographed on silica gel bythe flash method eluting with 4:1 hexane/ethyl acetate to give the titlecompound as an amorphous foam.

Anal. Calcd. for C₂₂H₂₀ON₃Cl₂F₃, 469.0935. Found: 469.0889.

EXAMPLE 7 A. 5-Amino-3-hydroxy-1-(2,4,6-trichlorophenyl)-pyrazole

Cyanoacetic acid (8.5 g, 0.10 mol) in 200 mL of dry ether was treatedwith 20.8 g (0.10 mol) of phosphorous pentachloride, warmed briefly toreflux and let cool to room temperature at which time all of thephosphorous pentachloride, had dissolved. After a small amount ofinsoluble material was removed by filtration, the ether was removed onthe rotary evaporator. Then 100 mL of toluene was added and stripped toremove phosphorous oxytrichloride. The residual pale yellow oil wasimmediately dissolved in 50 mL of cold methylene dichloride and added toa cold suspension of 21.15 g (0.10 mol) of2,4,6-trichlorophenylhydrazine in 14.0 mL of triethylamine and 100 mL ofmethylene dichloride, keeping the temperature below 20° C. by use of anice bath. The reaction mixture was allowed to warm to room temperatureand stirred for one hour. Then 500 mL of cold water was added. Theprecipitated solid was filtered and washed with water and with a littlemethylene dichloride to give the intermediate2-cyano-N-(2,4,6-trichlorophenyl)acethydrazide, 14.92 g (54%), m.p.166-168° C.

Anal. Calcd. for C₉H₆ON₃: C, 38.81; H, 2.17; N, 15.09. Found: C, 38.83;H, 2.06; N, 14.81.

This material (14.92 g, 53 mmol) was dissolved in a solution of 2.80 g(0.12 mol) of sodium in 200 mL of methanol and refluxed for 4 hours.After stirring overnight at room temperature, the methanol was mostlyevaporated and the residues were poured into water. The aqueous layerwas extracted with ether and was then acidified with concentratedhydrogen chloride. The product was extracted into ethyl acetate. Theextracts were dried with brine and magnesium sulfate and evaporated togive a foam which crystallized from ether to give 12.28 g (93%) of thetitle product, m.p. 221-223° C.

Anal. Calcd. for C₉H₆ON₃: C, 38.81; H, 2.17; N, 15.09. Found: C, 38.81;H, 2.16; N, 14.84.

B. 3-Hydroxy-5-phthalimido-1-(2,4,6-trichlorophenyl)pyrazole

A mixture of 4.50 g (18.0 mmol) of the compound of Step A and 2.81 g(19.0 mmol) of phthalic anhydride in 40 mL of glacial acetic acid wasrefluxed for 4 hours and stirred overnight at room temperature. Abouttwo volumes of water were added dropwise and the resulting solid wasfiltered and washed with water. The damp solid was taken up in a littleethanol, filtered and washed with a little ethanol and ether, and airdried to give the title compound, 5.11 g (69%), m.p. 295-298° C. (dec).

Anal. Calcd. for C₁₇H₈O₃N₃Cl₃: C, 49.97; H, 1.97; N, 10.28. Found: C,49.28; H, 1.95; N, 10.06.

C.4-(2-Chlorobenzoyl)-3-hydroxy-5-phthalimido-1-(2,4,6-trichlorophenyl)pyrazole

Aluminum trichloride (2.34 g, 17.6 mmol) was added to a solution of2-chlorobenzoyl chloride in 60 mL of 1,1,2,2-tetrachloroethane and theresulting mixture was stirred for 30 minutes at room temperature. Then2.87 g of the compound of Step B was added all at once and the reactionmixture was refluxed overnight. The cooled mixture was poured into waterand the aqueous phase was extracted three times with ethyl acetate. Theorganic extracts were dried with brine and magnesium sulfate andevaporated to give a red oil which was taken up in methanol andcrystallized to give the title compound, 2.97 g (77%), m.p. 245 -246° C.

D.4-(2-Chlorobenzoyl)-3-ethoxy-5-phthalimido-1-(2,4,6-trichlorophenyl)pyrazole

A solution of 0.55 g (1.0 mmol) of the compound of Step C in 10 mL ofdry dimethyl sulfoxide was treated portionwise with 36 mg (1.5 mmol) ofsodium hydride and the resulting mixture was stirred for 30 minutes atroom temperature. Then 0.21 mL (0.25 g, 1.61 mmol) of diethyl sulfatewas added and the reaction mixture was stirred for one hour at roomtemperature. The reaction mixture was poured into water and the productwas extracted into ethyl acetate. The extracts were washed with waterand dried with brine and magnesium sulfate, and evaporated to a gum. Theproduct was crystallized from boiling ethanol to give the product (230mg, 40%) as fine crystals, m.p. 215-216° C.

E. 5-Amino-4-(2-chlorobenzoyl)-3-ethoxy-1-(2,4,6-bZtrichlorophenyl)pyrazole

A suspension of 184 mg of the compound of Step D in 10 mL of ethanol wastreated with 0.5 mL of 55% hydrazine hydrate and refluxed for 1 hour.Solids in the cooled reaction mixture were filtered off and discardedand the filtrate was evaporated to a gum which was triturated with etherand filtered. The filtrate was again evaporated to a foam which wasshown to be 104 mg of the analytically pure title compound.

Anal. Calcd. for C₁₈H₁₃O₂N₃Cl₄: C, 48.57; H, 2.94; N, 9.44. Found, C,48.41; H, 2.52; N, 9.43.

EXAMPLE 85-Dimethylamino-4-(2-chlorobenzoyl)-3-methoxy-1-(2,4,6-trichlorophenyl)pyrazole

A solution of 60 mg (0.14 mmol) of5-amino-4-(2-chlorobenzoyl)-3-methoxy-1-(2,4,6-trichlorophenyl) pyrazoleprepared according to Example 7 in 5 mL of dry dimethyl sulfoxide wastreated with 22 mg (0.88 mmol) of oil-free sodium hydride to give ayellow solution. After 1 hour at room temperature, 0.2 mL (0.46 g, 3.21mmol) of methyl iodide was added. After stirring for 5 hours, thereaction mixture was poured into water and the product was extractedinto ethyl acetate. After drying with brine and magnesium sulfate, thesolvent was removed to give the title product as a one-spot foam. ¹H-NMR(CDCl₃): 2.77 (6H, s), 3.63 (3H, s), 7.24-7.42 (4H, m), 7.48 (2H, s).

EXAMPLE 9 A. 3,3-Bis-ethoxy-2-(3-trifluoromethylbenzoyl)-acrylonitrile

Sodium (0.126 g, 5.5 mmol) was dissolved in 15 mL of ethanol and 20 mLof dioxane was added followed by 1.59 g (5.0 mmol) of3,3-bis-methylthio-2-(3-trifluoromethylbenzoyl)-acrylonitrile and thereaction mixture was refluxed for 4 hours and let stir overnight at roomtemperature. This compound was relatively unstable to aqueous conditionsand was not isolated as such. Instead, an aliquot of the mixture wasstripped and the product was identified by 300 MHz proton NMR: NMR(DMSO-d₆): 1.14 (6H, tJ=7), 3.45 (4H, q, J=7), 7.44-8.16 (4H, m).

B.5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-ethoxy-4-(3-trifluoromethylbenzoyl)pyrazole

An aliquot of the above solution of step A containing approximately twomillimoles of 3,3-bis-ethoxy-2-(3-trifluoromethylbenzoyl)acrylonitrilewas reacted with 0.49 g (2.0 mmol) of2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol underreflux overnight. The cooled mixture was poured into dilute hydrogenchloride (HCl) and the product was extracted into ethyl acetate (EtOAc),washed with water and brine, and dried over magnesium sulfate (MgSO₄).Chromatography on silica gel with 4:1 hexane/EtOAc gave the titleproduct, 320 mg (31%), m.p. 77-78° C. from pentane.

EXAMPLE 105-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2,5-dimethylbenzoyl)-3-ethoxypyrazole

A solution of 0.26 g (1.5 mmol) of 2,5-dimethylbenzoylacetonitrile, 0.34mL (0.31 g, 1.60 mmol) of tetraethylorthocarbonate and 0.30 mL (0.33 g,3.20 mmol) of acetic anhydride in 10 mL of EtOAc was refluxed overnight.The solvent was evaporated and 10 mL of absolute ethanol was added andthen stripped. The residues were dissolved in 10 mL of ethanol, 368 mg(1.5 mmol) of 2,6-dichloro-4-trifluoromethylphenyl-hydrazine and 0.7 mL(0.51 g, 5.0 mmol) of triethylamine were added, and the mixture wasrefluxed for 90 minutes. The mixture was poured into water, extractedwith EtOAc and the organic extracts were washed with dilute HCl andbrine, and dried over MgSO₄. Evaporation gave a gum which waschromatographed on silica gel with 4:1 hexane/EtOAc to give the titleproduct which crystallized from pentane, 15 mg (2%), m.p. 99-101° C.

EXAMPLE 111-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methyl-4-(3-methylbenzoyl)-3-methylthiopyrazole

A solution of 2.97 g (16.9 mmol) of 4-(3-methylphenyl)butane-2,4-dioneand 4.04 mL (5.14 g, 67.6 mmol) of carbon disulfide in 60 mL of drydimethyl sulfoxide was treated portionwise with 0.89 g (37.1 mmol) ofoil-free sodium hydride at 15-18° C. After stirring 30 minutes, 2.31 mL(5.27 g, 37.1 mmol) of methyl iodide was added dropwise and the reactionmixture was allowed to stir at room temperature for 1 hour. It was thenpoured into water and the product was extracted into ether, backwashedwith water and dried over MgSO₄ to give 4.30 g (91%) of an oil whichcrystallized in the refrigerator overnight, m.p. 44-46° C. ¹H-NMR(CDCl₃): 2.16 (3H, s), 2.38 (6H, s), 2.72 (3H, s), 7.26-7.38 (2H, m),7.58-7.74 (2H, m). A mixture of 1.95 g (6.96 mmol) of3,3-bismethylthio-2-(3-methylbenzoyl)-2-acetylethene and 1.71 g of2,6-dichloro-4-trifluoromethylphenylhydrazine in 20 mL of ethanol wasrefluxed for 6 hours and then stirred at room temperature for 48 hours.The reaction mixture was poured into dilute HCl solution and the productwas extracted into EtOAc. The solution was dried and concentrated andthe residues were chromatographed on silica gel with 10:1 hexane/EtOActo give the title product which crystallized from pentane, 1.67 g (52%),m.p. 103-104° C.

EXAMPLE 125-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(5-[3-hydroxypropyl]-2-methylbenzoyl)-3-methylthiopyrazole

A solution of 0.530 g (1.0 mmol) of5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(5-[β-methoxycarbonylethyl]-2-methylbenzoyl)-3-methylthiopyrazolein 10 mL of THF was cooled in an ice bath while 1.33 mL of a 1.5 Msolution of DIBAL in THF was added. The reaction mixture was warmed toroom temperature and then quenched with water. The product was extractedinto EtOAc, dried and concentrated. The residues were chromatographed onsilica gel using mixtures of hexane/EtOAc to elute the title productwhich was isolated as an amorphous foam, 174 mg (34%).

Anal. Calcd. for C₂₂H₂₀O₂N₃SCl₂F₃: C, 50.97; H, 3.88; N, 8.10. Found, C,51.10; H, 3.96; N, 7.60.

EXAMPLE 13[5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfonyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanone

To a solution of 200 mg (0.42 mmol) of[5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylsulfanyl-1H-pyrazol-4-yl]-(2,5-dimethylphenyl)methanonein 10 mL of THF: was added 0.176 g (2.10 mmol) of anhydrous sodiumbicarbonate followed by a solution of 145 mg (0.42 mmol) of3-chloroperoxybenzoic acid in 8 mL of THF. After two hours at roomtemperature, 0.5 g of sodium bicarbonate and an additional 290 mg (0.84mmol) of 3-chloroperoxybenzoic acid was added. The reaction mixture washeated briefly to 50° C., let cool and stirred overnight at roomtemperature. The reaction mixture was added to water and the product wasextracted into ethyl acetate. The organic extracts were washed withdilute sodium bicarbonate solution and then dried and evaporated. Thetitle compound was crystallized from ether to give 150 mg (70% yield) ofcolorless crystals, m.p. 193.5-194.5° C.

EXAMPLE 14

The following compounds in Tables 1 and 2 were prepared according to theindicated Example.

TABLE 1

Process Physical Data of R₁ R₂ R₁₃ R₁₄ R₁₅ R₁₁ R₁₂ (m.p. in ° C.)Example amino SCH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. 178-180 1 amino SCH₃ 2-Cl4-Cl 6-Cl H H m.p. 178-180 1 amino SCH₃ 4-CF₃ H H 2-Cl H m.p. 150-153 1amino SCH₃ 2-Cl 4-Cl 6-Cl 2-F H m.p. 204-206 1 NHCH₃ SCH₃ 2-Cl 4-Cl 6-Cl2-Cl H m.p. 135-137 2 N(CH₃)₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. 194-197 2N(CH₃)₂ CH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. 220-222 6 amino SCH₃ 2-CF₃ H H2-Cl H m.p. 186-188 1 amino SCH₃ 2-Cl 4-Cl 6-Cl 2- H m.p. 165-167 1cyclopropyl amino SCH₃ 2-Cl 4-Cl 6-Cl 4-CH₃ H m.p. 230-232 1 amino SCH₃2-Cl 4-Cl 6-Cl 2-Cl 4-Cl m.p. Amorphous. 1 Anal. Calc'd forC17H10N30SCl5: C, 42.39; H, 2.09; N, 8.72. Found: C,41.94; H, 2.06; N,8.07. N(CH₃)₂ CH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. 108-109 6 NH₂ SCH₃ 2-F 4-F6-F 2-Cl H m.p. 156-158 1 N(CH₃)₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-F H m.p.Amorphous. 2 HRMS for C19H15N3OSCl3F Calc'd: 456.9984 Found: 456.9990NH₂ SCH₃ 2-Cl 6-Cl H 2-F H m.p. 182-184 1 NH₂ SCH₃ 2-F 4-F H 2-Cl H m.p.147-150 1 N(CH₃)₂ SCH₃ 2-Cl 4-Cl 6-Cl 3-Cl H m.p. 121-125 2 NH₂ NHCH₃2-Cl 4-Cl 6-Cl 2-Cl H m.p. 86-90 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-OCH₃ H m.p.200-202 1 NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 2-Cl H m.p. 207-210 1 NH(CH₂)₃OC₆H₅SCH₃ 2-Cl 6-Cl 4-Cl 2-Cl H m.p. Amorphous. 5 Anal. Calcd. forC26H21N3O2SCl4: C, 53.71; H, 3.64; N, 7.22. Found: C, 53.57; H, 3.41; N,7.46. NH₂ SCH₃ 2-Cl 6-Cl 4-Cl 3-CH₃ H m.p. 178-180 1 NH₂ SCH₃ 2-Cl 6-Cl4-CF₃ 3-Cl H m.p. 149-151 1 NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 3-CH₃ H m.p.150-153 1 N(CH₃)₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 3-Cl H m.p. 120-122 2 NH₂ SCH₃2-Cl 6-Cl 4-Cl 3-CF₃ H m.p. 158-160 1 NHCH₂COOH SCH₃ 2-Cl 6-Cl 4-Cl 2-ClH m.p. > 250 1 HRMS for C₁₉H₁₃N₃O₃SCl₄: Calcd: 525.9930 Found: 525.9348NH₂ SCH₃ 2-Cl 6-CF₃ 4-Cl 3-CF₃ H m.p. Amorphous. 1 Anal. Calcd. forC19H11N3OSCl2F6: C, 44.30; H, 2.15; N, 8.15. Found: C, 44.51; H, 2.29;N, 7.98 NH₂ SCH₃ 2-CH₃ 4-Cl H 2-Cl H m.p. 125-129 1 NH₂ SCH₃ 2-CH₃ 4-ClH 3-Cl H m.p. 112-115 1 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃ 5-CH₃ m.p.130-132 1 NH₂ SCH₃ 2-CH₃ 6-CH₃ H 3-Cl H m.p. 148-151 1 N(CH₃)₂ SCH₃ 2-Cl4-CF₃ 6-Cl 3-CF₃ H m.p. Amorphous. 2 Anal. Calcd. for C21H15N3OSCl2F6:C, 46.50; H, 2.78; N, 7.74. Found: C, 46.75; H, 2.93; N, 7.58 NH₂ SCH₃2-Cl 4-CF₃ H 3-Cl H m.p. 124-127 1 NH₂ SCH₃ 2-CH₃ 6-CH₃ H 3-Cl H m.p.139-142 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-CH₃ 5-CH₃ m.p. 182-184 1 CH₃ SCH₃2-Cl 4-Cl 6-Cl 3-CH₃ H m.p. 116-117 NH₂ SCH₃ 2-CH₃ 4-Cl 6-CH₃ 3-CF₃ Hm.p. Amorphous. 1 Anal. Calcd. for C20H17N3OSClF3: C, 54.48; H, 3.88; N,9.53. Found: C, 54.60; H, 3.91; N, 9.08 NH₂ SCH₃ 2-CH₃ 4-Cl 6-CH₃ 3-Cl Hm.p. Amorphous. 1 Anal. Calcd. for C19H17N3OSCl2: C, 56.16; H, 4.21; N,10.34. Found: C, 55.93; H, 4.21; N, 10.01 NH₂ SCH₃ 2-CH₃ 4-CH₃ 6-CH₃3-Cl H m.p. 163-165 1 NH₂ SCH₃ 2-CH₃ 4-CH₃ 6-CH₃ 3-CH₃ H m.p. 124-127 1NH₂ SCH₃ 2-CH₃ 4-CH₃ 6-CH₃ 3-CF₃ H m.p. 143-146 1 NH₂ SCH₃ 2-CH₃ 4-Br6-CH₃ 3-CF₃ H m.p. Amorphous. 1 Anal. Calcd. for C20H17N3OSBrF3: C,49.59; H, 3.53; N, 8.67. Found: C, 49.45; H, 3.49; N, 8.37 NH₂ SCH₃ 2-Cl4-CF₃ 6-Cl 2-CH₃ 3-CH₃ m.p. 196-198 1 NH₂ SCH₃ 2-CH₃ 4-Br 6-CH₃ 3-Cl Hm.p. Amorphous. 1 Anal. Calcd. for C19H17N3OSBrCl: C, 50.63; H, 3.80; N,9.32. Found: C, 50.40; H, 3.77; N, 8.94 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃5-(CH₂)₃— m.p. Amorphous. 1 CO₂CH₃ Anal. Calcd. for C24H22N3O3SCl2F 3:C, 51.43; H, 3.96; N, 7.50. Found: C, 51.59; H, 4.10; N, 7.17 NH₂ SCH₃2-CH₃ 6-CH₃ 4-Br 2-CH₃ 5-CH₃ m.p. Amorphous. 1 Anal. Calcd. forC₂₁H₂₂N₃OS: C, 56.76; H, 4.99; N, 9.45. Found: C, 56.37; H, 5.01; N,9.04 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-OCH₃ H m.p. 172-174 1 NH₂ OCH₃ 2-Cl 4-Cl6-Cl 2-Cl H m.p. Amorphous. 7 ¹H-NMR(CDCl₃): 3.68 (3H, s), 5.86(2H,broad s), 7.26- 7.44(4H, m) 7.51(2H, s). NH₂ OCH₂CH₃ 2-Cl 4-Cl 6-Cl 2-ClH m.p. Amorphous. 7 Anal. Calcd. for C18H13N3O2Cl4: C, 48.57; H, 2.94;N, 9.44. Found: C, 48.41; H, 2.52; N, 9.43 N(CH₃)₂ OCH₃ 2-Cl 4-Cl 6-Cl2-Cl H m.p. Amorphous. 8 HRMS for C19H15N3O2Cl4: Calcd: 456.9913 Found:456.9960 NH₂ OCH₂CH₃ 2-Cl 4-CF₃ 6-Cl 3-CF₃ 5-CF₃ m.p. Amorphous. 1 Anal.Calcd. for C20H10N3OSCl2F9: C, 41.25; H, 1.73; N, 7.21. Found: C, 41.49;H, 2.01; N, 7.01 NH₂ OCH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. Amorphous. 7¹H-NMR(CDCl₃): 3.68 (3H, s), 5.86(2H, broad s), 7.26- 7.44(4H, m)7.51(2H, s). NH₂ OCH₂CH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. Amorphous. 7 Anal.Calcd. for C18H13N3O2Cl4: C, 48.57; H, 2.94; N, 9.44. Found: C, 48.41;H, 2.52; N, 9.43 N(CH₃)₂ OCH₃ 2-Cl 4-Cl 6-Cl 2-Cl H m.p. Amorphous. 8HRMS for C19H15N3O2Cl4: Calcd: 456.9913 Found: 456.9960 NH₂ OCH₂CH₃ 2-Cl4-CF₃ 6-Cl 3-CF₃ 5-CF₃ m.p. Amorphous. 1 Anal. Calcd. forC20H10N3OSCl2F9: C, 41.25; H, 1.73; N, 7.21. Found: C, 41.49; H, 2.01;N, 7.01 NH₂ OCH₂CH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃ 5-CH₃ m.p. Amorphous. 1 HighResolution Mass Spectrum Calcd. for C22H20N3OCl2F3: 472.0806. Found,472.0817 NH₂ CH₂CH₂— 2-Cl 4-CF₃ 6-Cl 2-CH₃ 5-CH₃ m.p. Amorphous. 6 CH₃High Resolution Mass Spectrum Calcd. for C₂₁H₂₀N₃OC₁₂F₃: 469.0935.Found: 469.0889 NH₂ CH₂CH₂— 2-Cl 4-Cl 6-Cl 2-CH₃ 5-CH₃ m.p. Amorphous. 6CH₃ High Resolution Mass Spectrum Calcd. for C22H20N3OCl2F3: 436.0761.Found: 436.0764 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 3-OCH₃ H m.p. Amorphous. 3¹H-NMR(CDCl₃) δ 2.38(3H, s), 3.90(3H, s), 5.79(2H, broad s), 7.07(1H, d,J = 7), 7.16(1H, s), 7.23(1H, d, J = 7), 7.39(1H, t, J = 7), 7.79(2H, s)NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃ 5- m.p. Amorphous. 12  (CH₂)₄OH HighResolution Mass Spectrum Calcd. for C23H22N3O2SCl2F 3: 532.0840. Found:532.0871 NH₂ CH₂CH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃ 5-CH₃ m.p. Amorphous. 6 Anal.Calcd. for C21H18N3OCl2F3: C, 55.29; H, 3.97; N, 8.21. Found: C, 55.62;H, 4.35; N, 8.15 NH₂ CH₂CH₃ 2-Cl 4-Cl 6-Cl 2-CH₃ 5-CH₃ m.p. Amorphous. 6Anal. Calcd. for C20H18N3OCl3: C, 56.81; H, 4.29; N, 9.94. Found: C,56.88; H, 4.09; N, 9.62 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-CF₃ 5-CF₃ m.p.Amorphous. 1 Anal. Calcd. for C20H20N3OSCl2F9: C, 41.25; H, 1.71; N,7.21. Found: C, 41.20; H, 1.87; N, 6.89 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃5-CH₂CO₂— m.p. Amorphous. 1 C₂H₅ Anal. Calcd. for C23H20N3O3SCl2F 3: C,50.55; H, 3.68; N, 7.69. Found: C, 50.50; H, 3.50; N, 7.29 NH₂ SCH₃ 2-Cl4-CF₃ 6-Cl 2-CH₃ 5- m.p. Amorphous. 12  (CH₂)₂OH HRMS forC21H18N3O2SCl2F 3 Calcd: 503.0646 Found: 503.0147 NH₂ SCH₃ 2-Cl 4-CF₃6-Cl 2-OCH₃ 5-OCH₃ m.p. Amorphous. 1 ¹H-NMR(CDCl₃) δ 2.30(3H, s),3.60(6H,s), 5.85(2H, broad s), 6.80- 6.96(3H, m), 7.74(2H, s). NH₂OCH₂CH₃ 2-Cl 4-CF₃ 6-Cl 3-CF₃ H m.p. 112-114 9 NH₂ OCH₂CH₃ 2-Cl 4-CF₃6-Cl 3-CF₃ H m.p. 77-78 9 NH₂ OCH₂CH₃ 2-Cl 4-CF₃ 6-Cl 3-CH₃ H m.p.103-104 9 NH₂ OCH₂CH₃ 2-CH₃ 4-Br 6-CH₃ 3-CF₃ H m.p. 158-160 9 NH₂ SCH₃2-Cl 4-CF₃ 6-Cl 2-CH₃ 5-isopropyl m.p. Amorphous. 1 Anal. Calcd. forC22H20N3OSCl2F3: C, 52.59; H, 3.98; N, 8.36. Found: C, 52.39; H, 4.01;N, 8.08 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-CH₃ 5- m.p. Amorphous. 12  (CH₂)₃OHAnal. Calcd. for C22H20N3O2SCl2F 3: C, 50.97; H, 3.88; N, 8.10. Found:C, 51.10; H, 3.96; N, 7.60 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-COOC₂H₅ H m.p.211-216 1 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl R₁₁ and R₁₂ H m.p. 115-118 1 with thephenyl to which they are attached form 1- naphthyl NH₂ SCH₃ 2-Cl 4-CF₃6-Cl 3-Br H m.p. Amorphous. 1 Calcd. for C18H11N3OSBrCl2F 3C 41.16, H2.11, N 8.00. Found C 41.37, H 1.92, N 7.85. NH₂ SCH₃ 2-Cl 4-SO₂— 6-Cl3-CF₃ H m.p. 272-274 1 NH₂ NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 3-SO₂NH₂ H m.p.99-100 1 NH₂ SCH₃ 2-CH₃ 4-Br 6-CH₃ 3-SO₂NH₂ H m.p. 242-244 1 NH₂ SCH₃2-Cl 4-CF₃ 6-Cl 3- H m.p. Amorphous. 1 SO₂N(CH₃)₂ Anal. Calcd. forC20H17N4O3S2Cl2 F3/1/4C4H10O: C, 44.10; H, 3.44; N, 9.80. Found: C,43.88; H, 3.29; N, 9.68 NH₂ SCH₃ 2-CH₃ 4-Br 6-CH₃ 3- H m.p. Amorphous. 1SO₂N(CH₃)₂ Anal. Calcd. for C21H23N4O3S2Br: C, 48.18; H, 4.43; N, 10.70.Found: C, 48.42; H, 4.24; N, 10.52 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 3- H m.p.192-194 1 SO₂N(CH₃)₂ NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-(2-thienyl) H m.p.171.5-172.5 1 NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ H H m.p. 192-194 1 NH₂ CH₃ 2-Cl6-Cl 4-CF₃ 2-CH₃ 5-CH₃ m.p. 175-176 6 NH₂ CH₃ 2-CH₃ 6-CH₃ 4-Br 2-CH₃5-CH₃ m.p. 158-160 6 NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 3-N(CH₃)₂ H HRMS for 1C₂₀H₁₇ON₄SCl₂F₃ Calcd: 488.0452 Found: 488.0408 NH(C₃H₇) SCH₃ 2-Cl 6-Cl4-Cl 2-Cl H Calcd. C, 49.10; H, 5 3.50; N, 8.54; Found: C, 50.37; H,3.28; N, 8.47. NH₂ SO₂CH₃ 2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-CH₃ m.p. 193.5-194.513  NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 3-phenyl H m.p. 124-127 1 NH₂ SCH₃ 2-Cl6-Cl 4-CF₃ 2-pyrrolyl H HRMS Calcd. 1 510.0295 Found 510.0455N(CH₃)(C₂H₅) SCH₃ 2-Cl 6-Cl 4-Cl 2-Cl H FAB Mass Spectrum: 5 490 NH₂SCH₃ 2-Cl 6-Cl 4-Cl 2-CH₃ 5-iPr HRMS Calcd. 1 467.0393 Found 467.0395NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-n-butyl HRMS Calcd. 1 515.0809 Found515.0892 N(C₂H₅)₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-iPr HRMS Calcd. 5557.1277 Found 557.1287 NH₂ CH₃ 2-Cl 6-Cl 4-Cl 2-CH₃ 5-iPr HRMS Calcd. 1435.0669 Found 435.0682 N(C₂H₅)(C₃H₇) SCH₃ 2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-iPrMS parent 571, 529, 5 494, 360, 160 (100%) N(C₂H₅) (sec- SCH₃ 2-Cl 6-Cl4-CF₃ 2-CH₃ 5-iPr HRMS Calcd. 5 butyl) 585.1589 Found 585.1500N(CH₃)(C₂H₅) SCH₃ 2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-iPr HRMS Calcd. 5 543.1121Found 543.1166 N(C₂H₅)(C₃H₇) SCH₃ 2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-iPr HRMSCalcd. 5 569.1277 Found 569.1433 NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃ 2-n-propyl5-CH₃ HRMS Calcd. 1 501.0653 Found 501.0551 NH₂ SCH₃ 2-Cl 6-Cl 4-CF₃2-CH₃ 5-n-propyl HRMS Calcd. 1 501.0653 Found 501.0698 N(CH₃)(C₂H₅) SCH₃2-Cl 6-Cl 4-CF₃ 2-CH₃ 5-iPr HRMS Calcd. 5 555.1121 Found 555.0756 NH₂SCH₃ 2-Cl 4-Cl 6-Cl 2-CH₃ 6-CH₃ HRMS Calcd. 1 439.0080 Found 439.0097NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-Cl 6-Cl m.p. 212-213 1 NH₂ SCH₃ 2-CH₃ 4-Br6-CH₃ 2-Cl 6-Cl m.p. 252-254 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-Cl 6-Cl m.p.237-239 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-OCH₃ H m.p. 168-171 1 NH₂ SCH₃ 2-Cl4-CF₃ 6-Cl 2-OiPr 5-Cl MS 537 (parent ion) 1 480, 341 (100%), 308, 255,155 NH₂ SCH₃ 2-CH₃ 4-Br 6-CH₃ 2-OCH₃ 5-Br m.p. 191-193 1 NH₂ SCH₃ 2-Cl4-CF₃ 6-Cl 2-OCH₃ 5-Br m.p. 192-194 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-OCH₃5-Br m.p. 218-220 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-Br 5-Br m.p. 229-231 1 NH₂SCH₃ 2-Cl 4-CF₃ 6-Cl 2-Br 5-Br m.p. 172-174 1 NH₂ SCH₃ 2-CH₃ 4-Br 6-CH₃2-Br 5-Br m.p. 179-181 1 NH₂ SCH₃ 2-CH₃ 4-CH₃ 6-CH₃ 2-Br 5-Br m.p.195-197 1 NH₂ SCH₃ 2-CH₃ 4-Br 6-CH₃ 2-CH₃ 5-NO₂ m.p. 118-119 1 NH₂ SCH₃2-Cl 4-Cl 6-Cl 2-C₂H₅ H m.p. 146-150 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-CF₃ Hm.p. 175-177 1 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl 2-Cl 5-NO₂ m.p. 98.0-98.5 1 NH₂SCH₃ 2-CH₃ 4-Br 6-CH₃ 2-Cl 5-NO₂ m.p. 116-118 1 NH₂ SCH₃ 2-Cl 4-CF₃ 6-Cl2-CH₃ 5-NO₂ m.p. 99-100 1 NH₂ SCH₃ 2-CH₃ 4-CH₃ 6-CH₃ 2-CH₃ 5-NO₂ m.p.193-195 1 NH₂ SCH₃ 2-Cl 4-Cl 6-Cl 2-OC₃H₇ H ¹H-NMR (CDCl₃) δ 1 0.87 (3H,t, J = 7), 1.68(2H, m), 2.32(3H, s), 3.96(2H, q, J = 7), 5.80 (1H, broads), 6.93 (1H, d, J = 7), 7.03 1H, t, J = 7), 7.27 (1H, d, J = 7), 7.42(1H, t, J = 7), 7.52 (2H, s)

TABLE 2

Process Phys. Data of Ex- R₃ R₄ (m.p. in ° C.) ample C₂H₅CHC₄H₉2,6-Cl₂-4-CF₃Ph HRMS Calcd. 1 467.0809. Found 467.0913. C₃H₇CH═CH—C₂H₅2,6-Cl₂-4-CF₃Ph FAB Mass 1 Spectrum: 466 2- 2,4,6-Cl₃Ph HRMS Calcd. 1methylcyclopentyl 417.0236. Found 417.0328. 2-OC₂H₅-1-naphthyl2,6-Cl₂-4-CF₃Ph m.p. 149-151 1 2-OC₂H₅-1-naphthyl 2,4,6-Cl₃Ph m.p.125-128 1 3-CF₃-Ph 1,3-(CH₃)₂-4-NO₂— Calcd. for 1 pyrazol-5-ylC₁₇H₁₅O₃N₆SF₃: C, 46.36; H, 3.43; N, 19.08. Found: C, 46.51; H, 3.37; N,18.10.

EXAMPLE 15 A. 3-Trifluoromethylphenylthioacetonitrile

To sodium (0.62 g, 27.0 mmol) dissolved in 40 mL of ethanol was added4.79 g (26.9 mmol) of 3-trifluoromethylthiophenol and 2.04 g (27.0 mmol)of chloroacetonitrile. The reaction mixture was heated at reflux for 1hour and then stirred overnight at room temperature. To the cooledreaction mixture was added one volume of ether and the precipitatedsolids were removed by filtration. The filtrate was evaporated on therotary evaporator to give the product as an oil in essentiallyquantitative yield. This material was used in the following reactionwithout further purification.

B. 3-Trifluoromethylphenylcyanomethylsulfoxide

A solution of 3.00 g (13.8 mmol) of3-trifluoromethylphenylthioacetonitrile in 130 mL of methylene chloridewas cooled to 5° C. under dry N₂ and treated with 4.89 g (28.35 mmol) ofm-chloroperbenzoic acid. The reaction mixture was stirred for 48 hoursat room temperature and then cooled in ice, after which the insolubleswere removed by filtration. The filtrate was washed with 10% sodiumsulfate solution until all traces of peroxides had been removed and thendried over magnesium sulfate and evaporated to a pale yellow oil whichwas used in the subsequent reaction without further purification.

C. 3,3-Bis-methylthio-2-(3-trifluoromethylphenylsulfonyl)acrylonitrile

A solution of 13.82 mmol (crude product) of3-trifluoromethylphenylcyanomethylsulfoxide in 30 mL of drydimethylsulfoxide and 1.25 mL (1.58 g, 20.7 mmol) of CS₂ was cooled toabout 15° C. in an ice bath under dry nitrogen. Then 0.99 g (41.5 mmol)of oil-free sodium hydride was added portionwise below 20° C. and thedeep red solution was let stir at room temperature for 75 minutes. Thereaction mixture was cooled to 15° C., quenched with 2.58 mL (5.89 g,41.5 mmol) of methyl iodide and let stir overnight at room temperature.The reaction mixture was poured into ice/water and let granulate for 3.5hours. The product was filtered and air dried to give 3.51 g (72%) ofthe product. The analytical sample was crystallized from EtOH/H₂O, m.p.109-110° C.

D.5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(3-trifluoromethylbenzenesulfonyl)-3-methylthiopyrazole

A suspension of 0.50 g (1.42 mmol) of3,3-bis-methylthio-2-(3-trifluoromethylphenylsulfonyl)acrylonitrile and0.35 g (1.42 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in10 mL of ethanol was heated at reflux for 2.5 hours, solution occurringas the reaction mixture was warmed. The mixture was stirred overnight atroom temperature and was then poured into cold water. The product wasextracted into ethyl acetate and the extracts were dried with magnesiumsulfate and evaporated. The residues were crystallized from ether, andthe product was filtered off and air dried to give 314 mg (40%) of thedesired product, m.p. 201-203° C. Anal. Calcd. for C₁₈H₁₁O₂N₃S₂Cl₂F₆: C,39.28; H, 2.02; N, 7.64. Found: C, 39.35; H, 2.19; N, 7.48.

E.5-Dimethylamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(benzenesulfonyl)-3-methylthiopyrazole

A solution of 0.241 g (0.5 mmol) of5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(benzenesulfonyl)-3-methylthiopyrazolein 5 mL of dry dimethylsulfoxide was treated with 36 mg (1.5 mmol) ofoil-free sodium hydride under dry nitrogen in a flame-dried flask atroom temperature. After 30 minutes, a clear, pale yellow solution hadformed. This solution was treated with 0.5 mL (8.0 mmol) of methyliodide and stirred for 1 hour. Then the reaction mixture was poured intowater and extracted twice with ethyl acetate. The combined extracts weredried with brine and with magnesium sulfate and evaporated. The residuescrystallized from ether to give the desired product in 81% yield, m.p.163-164° C.

EXAMPLE 16

The following compounds were prepared in accordance with Example 15.

M.P. (° C.) or R₁₁ R₁₃,R₁₄,R₁₅ R₁ Analysis H 2,4,6-trichloro NH₂ 161-162H 2,4,6-trichloro N(CH₃)₂ 200-202 2-(i-propyl) 2,4,6-trichloro NH₂180-182 2-OCH₃ 2,4,6-trichloro NH₂ 212-215 2-Cl 2,4,6-trichloro NH₂Anal. Calcd. for C₁₆H₁₁O₂N₃S₂Cl₄: C, 39.60; H, 2.39; N, 8.33. Found:C,39.76; H, 229; N, 8.69 H 2,6-Cl₂-4-CF₃ NH₂ 209.5-210.5 H 2,6-Cl₂-4-CF₃N(CH₃)₂ 163-164 3-CF₃ 2,6-Cl₂-4-CF₃ NH₂ 201-203 3-CF₃ 2,6-Cl₂-4-CF₃N(CH₃)₂ 137-138

EXAMPLE 174-(2-Chlorophenyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methylthiopyrazolo[3,4-d]pyrimidine

A suspension of 669 mg (1.39 mmol) of5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-chlorobenzoyl)-3-methylthiopyrazolein 5 mL of formamide was heated at 150° C. overnight. A pale yellowsolid precipitated upon cooling of the reaction mixture. A total of 50mL of water was added to the stirred suspension to complete theprecipitation of the product which was filtered off and washed withwater. An inseparable trace of starting material was observed in theproduct by thin layer chromatography (TLC) and so the above procedurewas repeated on the mixture giving a brown solid containing no trace ofstarting material. Trituration of this solid with methylene chloridegave a pale yellow solution which was concentrated to give the desiredproduct as a white crystalline solid, m.p. 156-158° C.

EXAMPLE 18

The following compounds were prepared in accordance with Example 17.

R₃ R₉ R₁₃ m.p.(° C.) or HRMS 2-Cl-Ph H Cl 193-195 3-Cl-Ph H Cl 171-1732-Cl-Ph H CF₃ 156-158 2-Cl-Ph OH Cl 313-316 2-Cl-Ph Cl Cl 193-1952-Cl-Ph 4- Cl 222-225 ethoxycarbonyl- piperazinyl 1-naphthyl H CF₃171-173 2-Cl-Ph CH₃ Cl 210-212 2-CH₃-5-iPrPh CH₃ Cl 141-1422,6-(CH₃)₂-Ph CH₃ Cl HRMS Calcd. 462.0239. Found, 462.0369. 2-(OC₂H₅)-PhCH₃ Cl 189.192 2-(OC₂H₅)-1- CH₃ Cl HRMS: Calcd.: naphthyl 528.0345Found: 528.0226 2-OCH₃-Ph CH₃ Cl 214-216 2-C₂H₅-Ph CH₃ Cl HRMS: Calcd.462.0239 Found: 462.0219 Ph CH₃ CF₃ 114-116 2,5-(CH₃)₂-Ph CH₃ CF₃ HRMS:Calcd. 497.0579 Found: 497.0602 2-CF₃-Ph CH₃ Cl HRMS: Calcd. 501.9800Found: 501.9778

What is claimed is:
 1. A composition for the treatment of (a) illnessesinduced or facilitated by corticotropin releasing factor or (b)stress-induced illnesses, which comprises a compound of the formula

wherein A and R₁ together with the carbons to which they are attachedform pyrimidinyl which is optionally substituted by R₅ which ishydrogen, C₁-C₆ alkyl, fluoro, chloro, bromo, hydroxy, amino, O(C₁-C₆alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl), SH, S(O)_(n)(C₁-C₆alkyl) wherein n=0,1 or 2, wherein said C₁-C₆ alkyl optionally containsfrom one to two double or triple bonds and is optionally substituted byfrom 1 to 3 substituents R₆ which is hydroxy, amino, C₁-C₃ alkoxy,dimethylamino, diethylamino, methylamino, ethylamino, NH(C═O)CH₃,fluoro, chloro, bromo or C₁-C₃ thioalkyl; R₂ is hydrogen, C₁-C₆ alkyl,hydroxy, amino, O(C₁-C₆ alkyl), NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆alkyl), SH, S(O)_(n)(C₁-C₆ alkyl) wherein n=0,1, or 2, cyano, hydroxy,carboxy, or amido, wherein said alkyls are optionally substituted by oneto three of hydroxy, amino, carboxy, amido, NH(C═O)(C₁-C₆ alkyl),N(C₁-C₆ alkyl)(C₁-C₆ alkyl), (C═O)O(C₁-C₆ alkyl), C₁-C₃ thioalkyl,fluoro, bromo, chloro, iodo, cyano or nitro; R₃ is phenyl naphthyl, 3 to8-membered cycloalkyl or 9 to 12 membered bicycloalkyl, wherein each oneof the above groups is optionally substituted independently by from oneto three of fluoro, chloro, bromo, trifluoromethyl, C₁-C₆ alkyl or C₁-C₆alkoxy, or one of cyano, nitro, amino, NH(C₁-C₆ alkyl), N(C₁-C₄alkyl)(C₁-C₂ alkyl), COO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl), SO₂NH(C₁-C₄alkyl), SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), SO₂NH₂, NHSO₂(C₁-C₄ alkyl),S(C₁-C₆ alkyl), SO₂(C₁-C₆ alkyl), wherein said C₁-C₄ alkyl and C₁-C₆alkyl are optionally substituted by one or two of fluoro, chloro,hydroxy, amino, methylamino, dimethylamino or acetyl; and R₄ is phenyl,naphthyl, 3 to 8-membered cycloalkyl or 9 to 12-membered bicycloalkyl,wherein each of the above groups is optionally substituted independentlyby from one to three of fluoro, chloro, bromo, trifluoromethyl, C₁-C₆alkyl or C₁-C₆ alkoxy, or one of cyano, nitro, amino, NH(C₁-C₆ alkyl),N(C₁-C₄ alkyl)(C₁-C₂ alkyl), COO(C₁-C₄ alkyl), CO(C₁-C₄ alkyl),SO₂NH(C₁-C₄ alkyl), SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), SO₂NH₂, NH₂SO₂(C₁-C₄alkyl), S(C₁-C₆ alkyl), SO₂(C₁-C₆ alkyl), wherein said C₁-C₄ alkyl andC₁-C₆ alkyl are optionally substituted by one or two of fluoro, chloro,hydroxy, amino, methylamino, dimethylamino or acetyl; provided that R₄is not unsubstituted phenyl.
 2. A composition according to claim 1wherein R₃ is phenyl substituted independently with one or two offluoro, chloro, bromo, methyl, trifluoromethyl, nitro, C₁-C₆ alkyl,C₁-C₆ alkyloxy, SO₂NH₂, SO₂NH(C₁-C₆ alkyl), SO₂N(C₁-C₆ alkyl)₂, or R₃ isprimary, secondary or tertiary alkyl of from 4-9 carbon atoms whereinsaid C₄-C₉ alkyl may contain from one to two double or triple bonds andmay be substituted by from 1 to 3 substituents R₆ which is hydroxy,amino, C₁-C₃ alkoxy, dimethylamino, diethylamino, methylamino,ethylamino, NH(C═O)CH₃, fluoro, chloro, bromo, or C₁-C₃ thioalkyl.
 3. Acomposition according to claim 1 wherein R₄ is 2,4,6-trichlorophenyl,2,4,6-trimethylphenyl, 2,6-dichloro-4-trifluoromethylphenyl or4-bromo-2,6-dimethylphenyl.
 4. A composition according to claim 1wherein R₁ is amino, methylamino or dimethylamino.
 5. A compositionaccording to claim 1 wherein R₂ is methylthio or ethyl.
 6. A method forthe treatment of (a) illnesses induced or facilitated by corticotropinreleasing factor or (b) stress-induced illnesses, which comprisesadministering to a subject in need of such treatment a compound offormula 1 as defined in claim 1.